N-acetylcysteine conjugation

Like sulforaphane, however, PEITC-NAC (N-acetylcysteine) conjugate appears to block in Gl. Studies by Lund et al. show that in the case of the colorectal cell line HT29, which lacks wild type p53, treatment with AITC causes the cells to detach from the substratum but, at least in the short-term, they do not then enter apoptosis . Where it does occur, induction of apoptosis by isothiocyanate appears to be a p53-dependent process. However, this statement must also be qualified, because the effect appears to depend on which metabolite is considered. For example, sulforaphane does appear to be able to induce apoptosis in HT29 cells, which express a mutated form of the protein. 

CHIAO J W, CHUNG F, KRZEMINSKI J, AMIN S, ARSHAD R, AHMED, T aud CONAWAY C C (2000) Modulation of growth of human prostate cancer cells hy the N- acetylcysteine conjugate of pheuethyl isothiocyanate , Int J Oncol, 16 1215-9. 

Kassahun, K., Farrell, K. and Abbott, F. (1991) Identification and characterization of the glutathione and N-acetylcysteine conjugates of... 

The dog does, however, acetylate the Nl, sulfonamido group of sulfanilamide (chap. 4, Fig. 68), and also acetylates aliphatic amino groups. The guinea pig is unable to acetylate aliphatic amino groups such as that in cysteine. Consequently, it excretes cysteine rather than N-acetylcysteine conjugates or mercapturic acids. Birds, some amphibia, and insects are also able to acetylate aromatic amines, but reptiles do not use this reaction. 

The first two of these are discussed in chapter 4, and there are specific examples in chapter 7. The products are either excreted directly into the bile or further metabolized and excreted into the urine as cysteine or N-acetylcysteine conjugates. There are, however, examples of GSH conjugates being involved in toxicity as indicated in chapters 4 and 7. 

Although mercapturic acids, the N-acetylcysteine conjugates of xenobiotics, have been known since the early part of the twentieth century, only since the early 1960s has the source of the cysteine moiety (glutathione) and the enzymes required for the formation of these acids been identified and characterized. The overall pathway is shown in Figure 7.19. 

Hepatotoxicity due to valproate has been attributed to reactive hepatotoxic metabolites of valproate, which are normally detoxified by glutathione conjugation followed by mercapturic acid metabolism to their respective N-acetylcysteine conjugates (80). 

Gopaul SV, Farrell K, Abbott FS. Identification and characterization of N-acetylcysteine conjugates of valproic acid in humans and animals. Drug Metab Dispos 2000 28(7) 823-32. 

The toxicity induced by nephrotoxicant glutathione, cysteine, and N-acetylcysteine conjugates can be modified by a variety of compounds. Probenecid, an... 

The mercapturic acid pathway metabolites of menadione, the 3-glutathionyl and corresponding N-acetylcysteine conjugate (mercapturic acid) are a result of a detoxicative pathway designed to remove reactive electrophilic substrates from mammalian systems (10). The... 

LC/MS analysis of the N-acetylcysteine conjugate is shown in Figure 9. The base peak molecular ion was observed at m/z 334. Very little fragmentation occurred with the exception of a small amount of S-C cleavage to produce a protonated thiol at m/z 202. 

P Hu, L Jin, T Baillie. Studies on the metabolic activation of disulfiram in rat evidence for electrophilic S-oxygenated metabolites as inhibitors of aldehyde dehydrogenase and precursors of urinary N-acetylcysteine conjugates. J Pharmacol Exp Ther 281(2) 611—617, 1997. 

Conaway, C., Clifford, Wang, C.X., Pittman, B., Yang, Y.M., Schwartz, J.E., Tian, D., Mclntee, E. J., et al. 2006. Phenethyl isothiocyanate and sulforaphane and their N-acetylcysteine conjugates inhibit malignant progression of lung adenomas induced by tobacco carcinogens in A/J mice. Cancer Research, 65(18), 8548-57. doi 10.1158/0008-5472.CAN-05-0237. 

Figure 2.5 Human metabolism of isothiocyanate. Initial conjugation with glutathione occurs rapidly in an epithelial cell. Subsequent metabolism via the mercapturic acid pathway lead to N-acetylcysteine conjugates that are excreted in the urine.

Jiao, D., Ho, C.T., FoUes, P. et al. (1994) Identification and quantification of the n-acetylcysteine conjugate of aUyl isothiocyanate in human urine after ingestion of mustard. Cancer Epidemiol. Biomarkers Prev., 3,487-492. 

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